Though the effects of naturally occurring and synthetic cannabinoids have been well described, their mechanisms of action are just beginning to become known. Recent breakthrough demonstrating differences between the distribution of cannabinoid receptors and the receptor mRNA in the CNS strongly suggest the existence of cannabinoid neuronal pathways. The objectives of the research proposed in this project are to: 1) identify specific brain region which mediate the behavioral effects of the cannabinoids, and 2) characterize cannabinoid neuronal pathways. These proposed studies will focus on the hippocampus and basal ganglia because, in addition containing high concentrations of cannabinoid receptors and cannabinoid receptor mRNA, they mediate many of the behaviors associated with cannabinoid activity. The behavioral indices which will be assessed are the nociception, catalepsy, short-term memory, spontaneous activity, hypothermia, and rotational behavior. Using a pharmacological approach, which will include dose-response and SAR studies, the effects of cannabinoids in specific brain sites will be examined. In a separate series of studies, the neuronal pathways will be characterized by selective lesions of specific brain structures containing high concentrations of cannabinoid receptors or cannabinoid receptors mRNA. The methods of autoradiography and in situ hybridization histochemistry will then be used to assess changes in receptor number and expression of cannabinoid receptor mRNA, respectively. The results of this research will be an important first step in the elucidation of the neural substances of cannabinoid activity.